Phase IIb LUMINARA data presented at ESC Congress 2026 suggest that AZD5462 may improve cardiac remodeling and hemodynamics across different heart failure phenotypes, with the lowest dose producing the strongest remodeling signal in HFrEF.

An oral drug targeting the relaxin pathway has shown encouraging effects on cardiac function and vascular resistance in patients with chronic heart failure, according to results from the phase IIb LUMINARA trial presented during a Hot Line session at ESC Congress 2026¹ and simultaneously published in Circulation.²

AZD5462 is an oral, once-daily agonist of the relaxin family peptide receptor 1 (RXFP1). Activation of RXFP1 has been associated with vasodilation, reduced preload and afterload, and potential improvements in myocardial fibrosis and cardiac remodeling. Previous efforts to harness the relaxin pathway in heart failure have, however, been limited by either a lack of long-term benefit or safety concerns, including fluid retention.²

LUMINARA therefore investigated whether AZD5462 could provide the potential cardiovascular benefits of RXFP1 activation when added to contemporary guideline-directed medical therapy.

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Lowest dose produces strongest remodeling signal in HFrEF

The double-blind, placebo-controlled, dose-ranging study randomized 375 patients with chronic heart failure to AZD5462 20 mg, 80 mg or 360 mg once daily, or placebo. The trial included 235 patients with left ventricular ejection fraction (LVEF) ≤35% and 140 with LVEF 41–55%. The published study reports that patients were enrolled across 57 sites in 10 countries.

In patients with LVEF ≤35%, the primary endpoint was change in end-systolic volume index (ESVI), a measure of cardiac remodeling. After 24 weeks of treatment, the largest improvement was observed with the lowest, 20-mg dose. Compared with placebo, ESVI decreased by 5.4 mL/m² (95% CI, −10.9 to 0.1; p=0.054). The effect was smaller with increasing doses, suggesting an inverse dose-response relationship.

In patients with LVEF 41–55%, the primary endpoint was systemic vascular resistance index (SVRI), used to assess target engagement and vascular effects. Significant placebo-adjusted reductions in SVRI were observed with all three doses, corresponding to reductions of approximately 19%, 21% and 15% with the 20-, 80- and 360-mg doses, respectively.

Expert perspective

Speaking to touchCARDIO following the presentation, study presenter Prof. James Januzzi, Baim Institute for Clinical Research, Massachusetts General Hospital and Harvard Medical School, Boston, highlighted safety as one of the most important findings.

Q: What were the standout findings from LUMINARA?

Prof. Januzzi: “Use of oral relaxin in this study was very well tolerated by the study participants, which in itself is a very important finding given the recent studies with volenrelaxin, which found an unacceptably high rate of volume overload and heart failure hospitalization. We saw none of that.”

He added that the study demonstrated “significant amounts of reverse cardiac remodeling” in patients with reduced ejection fraction, particularly at the lowest dose, as well as evidence of target engagement and vasodilation in those with preserved ejection fraction.

Importantly, increasing doses were associated with greater activation of renin. The investigators suggest that the 20-mg dose may have provided sufficient reduction in afterload while producing less neurohormonal activation, whereas higher doses may have stimulated renin sufficiently to counter some of the beneficial effects. This explanation remains hypothesis-generating.

 Q: It is still early, but what potential could AZD5462 have in future clinical practice?

Prof. Januzzi: “Certainly among individuals with reduced ejection fraction, the amount of reverse remodeling we observed would be expected in outcome studies to be associated with a significant impact on prognosis.”

However, he stressed that clinical outcome data are now required.

“The only way to really know this for sure is to do a prospective outcome study. At this stage, that’s what’s needed — a prospective study focused on an appropriately powered number of individuals in order to better understand the impact of oral relaxin agonists, in this case AZD5462, on prognosis.”

AZD5462 was generally well tolerated. A modest reduction in blood pressure was observed, but there was no imbalance in reported hypotension events in the reduced-EF cohort. The authors also caution that LUMINARA was a relatively small phase II study based primarily on mechanistic endpoints, and several secondary measures did not consistently support the effects observed in the primary endpoints.

Larger and longer randomized trials will therefore be needed to establish whether the improvements in cardiac remodeling and hemodynamics seen in LUMINARA translate into reductions in heart failure hospitalization, mortality or other clinically meaningful outcomes.

References:

1. Januzzi JL Jr. LUMINARA: AZD5462 in patients with chronic heart failure. Presented during a Hot Line session at ESC Congress 2026; Munich, Germany; August 30, 2026.
2. Januzzi JL Jr, et al. Oral Relaxin Receptor Agonist AZD5462 in Participants With Chronic Heart Failure: Primary Results From the LUMINARA Trial. Circulation. 2026. doi:10.1161/CIRCULATIONAHA.126.082763.